The present invention relates to a novel method of treating diseases resulting from calcium metabolism disorders. More specifically, this invention relates to a method comprising the use of 26,26,26,27,27,27-hexafluoro-1.alpha.,25-dihydroxycholecalciferol, a derivative of vitamin D.sub.3.
Vitamin D.sub.3 is a well-known agent for the control of calcium and phosphorous homeostasis. It is also now well known that to be effective, vitamin D.sub.3 must be converted to its hydroxylated forms. For example, the vitamin is first hydroxylated in the liver to form 25-hydroxyvitamin D.sub.3 and is further hydroxylated in the kidney to produce 1.alpha.,25-dihydroxy vitamin D.sub.3 or 24,25-dihydroxy vitamin D.sub.3. The 1.alpha.-hydroxylated form of the vitamin is generally considered to be the physiologically active or hormonal form of the vitamin and to be responsible for what are termed the vitamin D-like activities, such as increasing intestinal absorption of calcium phosphate, mobilizing bone mineral, and reabsorbing calcium in the kidneys.
Since the discovery of biologically active metabolites of vitamin D.sub.3 there has been much interest in the preparation of structural analogs of these metabolites, because such compounds may represent useful therapeutic agents for the treatment of diseases resulting from calcium metabolism disorders. A variety of vitamin D-like compounds have been synthesized. See, for example, U.S. Pat. Nos. 3,741,996 directed to 1.alpha.-hydroxycholecalciferol; 3,907,843 directed to 1.alpha.-hydroxyergocalciferol; 3,786,062 directed to 22-dehydro-25-hydroxycholecalciferol; 3,906,014 directed to 3-deoxy-1.alpha.-hydroxycholecalciferol; and 4,069,321 directed to the preparation of various side chain-fluorinated vitamin D.sub.3 derivatives and side chain-fluorinated dihydrotachysterol analogs.
A fluoro derivative of the accepted hormonal form of vitamin D.sub.3, 1,25-dihydroxycholecalciferol (1,25-(OH).sub.2 D.sub.3), of particular interest is 24,24-difluoro-1,25-(OH).sub.2 D.sub.3 because it is characterized by at least as great if not greater activity than 1,25-(OH).sub.2 D.sub.3 (see U.S. Pat. No. 4,201,881).
Also of interest is the 26,26,26,27,27,27-hexafluoro derivative of 25-hydroxycholecalciferol (see U.S. Pat No. 4,248,791) and the 26,26,26,27,27,27-hexafluoro derivative of 1.alpha.,25-dihydroxycholecalciferol (see U.S. Pat. No. 4,358,406). The latter is characterized by substantially greater vitamin D-like activity than the hormonal form of vitamin D.sub.3, namely 1,25-dihydroxycholecalciferol, in its ability to stimulate calcium transport in the intestine, to mobilize calcium from bone and in its anti-rachitic activity according to the rat line test. In fact, data contained in U.S. Pat. No. 4,358,406 demonstrates that this latter hexafluoro derivative exhibits activity at least ten times greater than that of 1,25-(OH).sub.2 D.sub.3.
Several of these known vitamin D compounds exhibit highly potent activity in vivo or in vitro, and possess advantageous activity profiles and thus are in use, or have been proposed for use, in the treatment of a variety of diseases resulting from calcium metabolism disorders such as renal osteodystrophy, vitamin D-deficient rickets, and various type of osteoporosis. Vitamin D compounds have also been proposed for use in treating psoriasis, and certain malignancies.
It has generally been accepted, however, that increased toxicity also results from such increased activity. As a result, it is generally accepted that the administered dosage of highly active compounds needed to be appropriately reduced so as to avoid toxicity in a patient. Thus, the more highly active vitamin D compounds were no more effective in a patient than were the less active vitamin D compounds.
It is well known that females at the time of menopause suffer a marked loss of bone mass giving rise ultimately to osteopenia, which in turn gives rise to spontaneous crush fractures of the vertebrae and fractures of the long bones. This disease is generally known as postmenopausal osteoporosis and presents a major medical problem, both in the United States and most other countries where the life-span of females reaches ages of at least 60 and 70 years. Generally, the disease which is often accompanied by bone pain and decreased physical activity, is diagnosed by one or two vertebral crush fractures with evidence of diminished bone mass. It is known that this disease is accompanied by diminished ability to absorb calcium, decreased levels of sex hormones, especially estrogen and androgen, and a negative calcium balance.
Similar symptoms of bone loss characterize estrogen-lack osteoporosis, senile osteoporosis and steroid-induced osteoporosis, the latter being a recognized result of long term glucocorticoid (cortico-steroid) therapy for certain disease states.
Methods for treating osteoporosis have varied considerably but to date no totally satisfactory treatment is yet known. A conventional treatment is to administer a calcium supplement to the patient. However, calcium supplementation by itself has not been successful in preventing or curing the disease. Another conventional treatment is the injection of sex hormones, especially estrogen, which has been reported to be effective in preventing the rapid loss of bone mass experienced in postmenopausal women. This technique, however, has been complicated by the fear of its possible carcinogenicity. Other treatments for which variable results have been reported, have included a combination of vitamin D in large doses, calcium and fluoride. The primary problem with this approach is that fluoride induces structurally unsound bone, called woven bone, and in addition, produces a number of side effects such as increased incidence of fractures and gastrointestinal reaction to the large amounts of fluoride administered. Another suggested method is to block bone resorption by injecting calcitonin or providing phosphonates.
In a study using calcitriol, i.e. 1.alpha.,25-dihydroxyvitamin D.sub.3, Oloia et al, "Calcitriol In The Treatment Of Postmenopausal Osteoporosis," Amer. Jour. of Medicine, 1988, Vol. 84, pages 401-408, it was reported that calcitriol treatment reduced bone loss in women with postmenopausal osteoporosis by increasing calcium absorption and reducing bone resorption, but had no effect on bone formation. The average dose of calcitriol used in the Oloia et al study was 0.8 .mu.g per day. Hypercalciuria occurred in all subjects treated with calcitriol, and hypercalcemia occurred in 11 of 12 subjects. As a result, dietary calcium was lowered in each of the calcitriol treated patients. It was concluded in the Oloia et al study that further studies of efficacy and safety with lower dosages of calcitriol (up to 0.5 .mu.g per day) would be of interest.
In Tilyard et al, "Treatment of Postmenopausal Osteoporosis With Calcitriol Or Calcium," New England Journal of Medicine, 1992, Vol. 326, No. 6, pages 357-362, it was reported that women suffering from postmenopausal osteoporosis who received calcitriol, i.e. 1.alpha.,25-dihydroxyvitamin D.sub.3, at dosages of 0.5 .mu.g per day for three years had a significant reduction in the rate of new vertebral fractures over women who were treated over the same period of time with supplemental calcium in the form of 1 gram of elemental calcium daily. Calcitriol treatment of the women in the Tilyard et al study was not accompanied by hypercalcemia of any severity, and thus it was concluded that calcitriol given orally in a dose of 0.25 .mu.g twice a day to postmenopausal women with an average dietary calcium intake of 800 mg has limited potential to induce hypercalcemia. However, it was also concluded in the Tilyard et al study that serum calcium concentrations should be monitored in patients receiving calcitriol therapy due to the possibility of hypercalcemia as a side effect of such treatment.
In view of the results published by Oloia et al and Tilyard et al, calcitriol may be a viable therapeutic option in the treatment of women with postmenopausal osteoporosis. However, there is a relatively small dosage "window" or tolerance between effectiveness and toxicity resulting in the necessity to closely monitor calcitriol dosages as well as dietary calcium intake in order to avoid hypercalcemia. Thus, the potential of calcitriol to induce hypercalcemia has limited the use of calcitriol to treat postmenopausal osteoporosis as well as other diseases resulting from calcium metabolism disorders.
U.S. Pat. No. 4,255,596 suggests the use of various metabolites of vitamin D.sub.3 for increasing calcium absorption and retention within the body of mammals displaying evidence of or having a physiological tendency toward loss of bone mass. The metabolites specifically named in that patent, i.e., 1.alpha.-hydroxyvitamin D.sub.3, 1.alpha.-hydroxyvitamin D.sub.2, 1.alpha.,25-dihydroxyvitamin D.sub.3, 1.alpha.,25-dihydroxyvitamin D.sub.2 and 1,24,25-trihydroxyvitamin D.sub.3, although capable of the activity described and claimed in that patent, are also characterized by the disadvantage of causing hypercalcemia, especially if used with the conventional calcium supplement treatment. Therefore, use of these compounds to treat osteoporosis has not been widely accepted. U.S. Pat. Nos. 3,833,622 and 3,901,928 respectively suggest using the hydrate of 25-hydroxyvitamin D.sub.3 and 1.alpha.-hydroxyvitamin D.sub.3 for treatment of osteoporosis in a general expression of utility for those compounds. It is well known that both of those compounds express traditional vitamin D-like activity, including the danger of hypercalcemia.
U.S. Pat. No. 4,588,716 also suggests the use of 1.alpha.,25-dihydroxy-24-epi-vitamin D.sub.2 to treat bone disorders characterized by the loss of bone mass, such as osteoporosis. Although this compound expresses some of the vitamin D-like characteristics affecting calcium metabolism such as increasing intestinal calcium transport and stimulating the mineralization of new bone, it has the advantage of minimal effectiveness in mobilizing calcium from bone. The 24-epi compound may be administered alone or in combination with a bone mobilization-inducing compound such as a hormone or a vitamin D compound such as 1.alpha.-hydroxyvitamin D.sub.3 or -D.sub.2, or 1.alpha.,25-dihydroxyvitamin D.sub.3 or -D.sub.2.